U.S. patent number 5,356,896 [Application Number 07/995,252] was granted by the patent office on 1994-10-18 for stabilized pharmaceutical compositions comprising an hmg-coa reductase inhibitor compound.
This patent grant is currently assigned to Sandoz Ltd.. Invention is credited to Mohan B. Kabadi, Richard V. Vivilecchia.
United States Patent |
5,356,896 |
Kabadi , et al. |
October 18, 1994 |
Stabilized pharmaceutical compositions comprising an HMG-CoA
reductase inhibitor compound
Abstract
A pharmaceutical dosage form comprising an HMG-CoA reductase
inhibitor compound, e.g., fluvastatin sodium, is disclosed which is
stabilized against pH-related degradation by an alkaline
stabilizing medium capable of imparting a pH of at least 8 to an
aqueous solution or dispersion of the composition.
Inventors: |
Kabadi; Mohan B. (Marlboro,
NJ), Vivilecchia; Richard V. (Rockaway, NJ) |
Assignee: |
Sandoz Ltd. (Basel,
CH)
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Family
ID: |
36808687 |
Appl.
No.: |
07/995,252 |
Filed: |
December 22, 1992 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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805667 |
Dec 12, 1991 |
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Current U.S.
Class: |
514/256; 514/277;
514/970; 514/415; 514/306; 514/569 |
Current CPC
Class: |
A61P
43/00 (20180101); A61K 9/2009 (20130101); A61K
31/405 (20130101); A61K 9/1611 (20130101); A61P
3/14 (20180101); A61P 3/06 (20180101); A61P
9/10 (20180101); Y10S 514/97 (20130101) |
Current International
Class: |
A61K
9/16 (20060101); A61K 9/20 (20060101); A61K
31/405 (20060101); A61K 31/403 (20060101); A61K
031/505 (); A61K 031/435 (); A61K 031/44 (); A61K
031/405 (); A61K 031/19 () |
Field of
Search: |
;514/415,970,256,277,306,569 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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114027 |
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Jul 1984 |
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EP |
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375156 |
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Jun 1990 |
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EP |
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401705 |
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Dec 1990 |
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EP |
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Other References
CA 114 (6) 49589k, Dennick, 1990..
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Primary Examiner: Cintins; Marianne M.
Assistant Examiner: Jordan; Kimberly R.
Attorney, Agent or Firm: Honor; Robert S. Vila; Richard E.
Furman; Diane E.
Parent Case Text
This application is a continuation-in-part of application Ser. No.
07/805,667 filed Dec. 12, 1991 and now abandoned.
Claims
What is claimed is:
1. A pharmaceutical composition comprising an HMG-CoA reductase
inhibitor compound of the formula: ##STR4## wherein R is an organic
radical,
X is --CH.dbd.CH--, and
M is a physiologically acceptable cation,
and an alkaline stabilizing medium capable of imparting a pH of at
least 8 to an aqueous solution or dispersion of the composition
wherein the alkaline stabilizing medium comprises at least one
pharmaceutically acceptable carbonate salt.
2. A pharmaceutical composition according to claim 1 wherein R is
selected from the group consisting of indolyl, pyrimidinyl,
indenyl, pyridinyl and quinolinyl radicals and derivatives thereof,
and X is (E)--CH.dbd.CH--.
3. A pharmaceutical composition according to claims 2 wherein the
pharmaceutically acceptable carbonate salt is selected from the
group consisting of sodium carbonate, sodium bicarbonate, calcium
carbonate and mixtures thereof.
4. A pharmaceutical composition according to claim 1 wherein the
alkaline stabilizing medium comprises a mixture of a water soluble
carbonate and a water insoluble or sparingly soluble carbonate.
5. A pharmaceutical composition according to claim 4 wherein the
ratio of water soluble carbonate to water insoluble or sparingly
soluble carbonate is from 1:40 to 2:1.
6. A pharmaceutical composition comprising the HMG-CoA reductase
inhibitor fluvastatin sodium and a pharmaceutically acceptable
alkaline stabilizing medium capable of imparting a pH of at least 8
to an aqueous solution or dispersion of the composition.
7. A pharmaceutical composition according to claim 6 wherein the
alkaline stabilizing medium comprises at least one pharmaceutically
acceptable carbonate salt.
8. A pharmaceutical composition according to claim 7 wherein the
pharmaceutically acceptable carbonate salt is selected from the
group consisting of sodium carbonate, sodium bicarbonate, calcium
carbonate and mixtures thereof.
9. A pharmaceutical composition according to claim 8 comprising
fluvastatin sodium, (i) calcium carbonate and (ii) sodium carbonate
or sodium bicarbonate.
10. A pharmaceutical composition according to claims 1, 3, or 8
which comprises 0.5 to 60 wt. % HMG-CoA reductase inhibitor
compound, 0.5 to 40 wt. % calcium carbonate, 0.5 to 20 wt. % sodium
bicarbonate, and 10 to 65 wt. % microcrystalline cellulose.
11. A pharmaceutical composition according to claims 2 or 6 in
solid unit dosage form.
12. An oral pharmaceutical composition suitable for excapsulation
for delivering fluvastatin sodium which comprises 0.5 to 60 wt. %
of fluvastatin sodium,
25 to 40 wt. % of calcium carbonate,
0.5 to 10 wt. % of sodium bicarbonate, and
20 to 35 wt. % of microcrystalline cellulose.
13. An oral pharmaceutical composition suitable for tableting for
delivering fluvastatin sodium which comprises
0.5 to 60 wt. % of fluvastatin sodium,
5 to 20 wt. % of calcium carbonate,
5 to 20 wt. % of sodium bicarbonate, and
50 to 65 wt. % of microcrystalline cellulose.
14. A composition according to claim 12 wherein the capsule is
coated with an enteric and/or film coating.
15. A composition according to claim 13 wherein the tablet is
coated with an enteric and/or film coating.
16. A composition according to claim 12 wherein fluvastatin sodium
is present in a dosage amount selected from the group consisting of
5, 10, 15, 20 and 40 mg. amounts.
17. A composition according to claim 13 wherein fluvastatin sodium
is present in a dosage amount selected from the group consisting of
5, 10, 15, 20 and 40 mg. amounts.
18. A composition according to claims 2 or 8 wherein the HMG-CoA
reductase inhibitor compound and the pharmaceutically acceptable
carbonate salt are in intimate contacting association.
19. A method of preparing the composition of claims 2 or 8 which
comprises bringing the HMG-CoA reductase inhibitor compound and the
alkaline stabilizing medium into intimate contacting association by
co-lyophilizing the HMG-CoA reductase inhibitor compound and the
alkaline stabilizing medium.
20. A pharmaceutical composition according to claim 2 wherein the
HMG-CoA reductase inhibitor compound is a pharmaceutically
acceptable salt of
erythro-3R,5S-(E)-7-[4-fluorophenyl-6-(1-methylethyl)-2-(dimethylamino-pyr
imidin-5-yl)-3,5-dihydroxy-6-heptenoic acid, or its racemate.
21. A pharmaceutical composition according to claim 2 wherein the
HMG-CoA reductase inhibitor compound is a pharmaceutically
acceptable salt of
erythro-3R,5S-(E)-dimethoxy-7-[3'-(4"-fluorophenyl)-spiro[cyclopentane-1,1
'(1H)-inden]-2'-yl]-3-hydroxyhept-6-enoic acid, or racemate.
22. A pharmaceutical composition according to claim 2 wherein the
HMG-CoA reductase inhibitor compound is a pharmaceutically
acceptable salt of
erythro-3R,5S-(E)-7-[4-(4-fluorophenyl)-2,6-bis(1-methylethyl)-5-methoxyme
thyl-pyridin-3-yl]-3,5-dihydroxy-6-heptenoic acid, or its
racemate.
23. A pharmaceutical composition according to claim 2 wherein the
HMG-CoA reductase inhibitor compound is a pharmaceutically
acceptable salt of
erythro-(.+-.)-(E)-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-pyridin-
3-yl]-3,5- dihydroxy-6-heptenoic acid, or its 3R,5S isomer.
24. A pharmaceutical composition according to claim 2 wherein the
HMG-CoA reductase inhibitor compound is a pharmaceutically
acceptable salt of
erythro-(.+-.)-(E)-7-[4-(4-fluorophenyl)-2-(1-methylethyl)-quinolin-3-yl]-
3,5-dihydroxy-6- heptenoic acid, or its 3R,5S isomer.
25. A pharmaceutical composition according to claim 2 wherein the
HMG-CoA reductase inhibitor compound is a pharmaceutically
acceptable salt of
erythro-(.+-.)-(E)-7-[4-(4-fluorophenyl)-2-cyclopropyl-quinolin-3-yl]-3,5-
dihydroxy-6-heptenoic acid, or its 3R, 5S isomer.
26. A pharmaceutical composition according to claim 2 which
comprises
erythro-(E)-3R,5S-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-3
,5-dihydroxy-6-heptenoic acid, sodium salt.
27. A pharmaceutical composition according to claims 2 or 7 which
comprises 0.5 to 60 wt. % HMG-CoA reductase compound, 10 to 55 wt.
% pharmaceutically acceptable carbonate salts, and 10 to 65 wt. %
filler.
Description
The present invention relates to a pharmaceutical composition
comprising a pH sensitive medicament, which has enhanced storage
stability.
Certain HMG-CoA reductase compounds, i.e. cholesterol biosynthesis
inhibitors, useful in the treatment of hyperlipoproteinemia and
atherosclerosis, which are compounds of the formula ##STR1##
wherein R is an organic radical,
X is --CH.sub.2 --CH.sub.2 -- or --CH.dbd.CH--, preferably
(E)--CH.dbd.CH--, and
M is a physiologically acceptable cation, such as an alkali metal
cation or ammonium, preferably sodium or potassium, and especially
sodium,
are extremely susceptible to degradation at pH below about 8. An
example of such a compound comprises the compound having the USAN
designation fluvastatin sodium (hereinafter "fluvastatin"), of the
formula: ##STR2## [i.e. erythro-R*,
S*-(E)-(.+-.)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-3,5-d
ihydroxy-6-heptenoic acid, sodium salt]. The above-indicated
erythro racemate may be resolved into two optically pure
enantiomers, the 3R,5S and 3S,5R isomers, of which the former is
preferred [see European Patent Application EP-A-114,027].
For example, we have found that the degradation kinetics of
fluvastatin in aqueous solution at various pH are as illustrated
below:
______________________________________ % fluvastatin remaining at
37.degree. C. pH after 1 hour after 24 hrs
______________________________________ 7.8 98.3 98.0 6.0 99.6 97.1
4.0 86.7 25.2 1.0 10.9 0 ______________________________________
The above-indicated instability of fluvastatin and related HMG-CoA
reductase compounds we believe is due to the extreme lability of
the .beta.,.delta.-hydroxy groups on the heptenoic acid chain and
the presence of the double bond, such that at neutral to acidic pH,
the compounds readily undergo elimination or isomerization or
oxidation reactions to form conjugated unsaturated aromatic
compounds, as well as the threo isomer, the corresponding lactones,
and other degradation products.
In order to achieve marketable dosage forms comprising such a
compound, it is essential to adequately protect it against
pH-related destabilization.
Additionally, the heat and light sensitivity as well as
hygroscopicity of the subject compounds impose particular
requirements in the manufacture and storage of pharmaceutical
dosage forms.
We have surprisingly been able to prepare such compositions having
extended periods of storage stability, e.g., whereby at least about
95% of the initial amount of the drug is active after 2 years at
+25.degree. C. and +30.degree. C. and for longer periods.
Compositions of the invention on oral administration can provide
rapid and essentially complete intestinal absorption of drug
substance.
It is a further advantage that the stabilized compositions of the
invention can be readily prepared by aqueous or other solvent-based
techniques, e.g. wet granulation.
In one aspect the present invention provides a pharmaceutical
composition comprising an HMG-CoA compound of the formula ##STR3##
wherein R is an organic radical, preferably free of acidic
groups
X is --CH.dbd.CH--, preferably (E)--CH.dbd.CH--, and
M is a physiologically acceptable cation,
and an alkaline stabilizing medium capable of imparting a pH of at
least 8 to an aqueous solution or dispersion of the
composition.
The compositions comprise the drug substance and an "alkaline
stabilizing medium," said alkaline medium being capable of
stabilizing the composition by imparting a pH of at least 8 to an
aqueous solution or dispersion of the composition. Preferably the
compounds of formula I and the alkaline medium are in intimate
contacting association in the composition to achieve optimal
stability of the medicament.
The resulting composition has been found to provide an extended
storage life of the compounds of formula I, even in the presence of
moisture or when such compositions additionally comprise otherwise
potentially reactive excipients, such as lactose. The stability of
the drug substance in compositions of the invention can be at least
95%, and is typically between 98% and 99%, after 18 months at
25.degree. C., and for even longer periods.
The terms "alkaline stabilizing medium," "alkaline medium" or
"base" employed herein shall refer to one or more pharmaceutically
acceptable substances capable of imparting a pH of at least 8, and
preferably at least 9, and up to about pH 10, to an aqueous
solution or dispersion of the composition of the invention. More
particularly, the alkaline stabilizing medium creates a "micro-pH"
of at least 8 around the particles of the composition when water is
adsorbed thereon or when water is added in small amounts to the
composition. The alkaline medium should otherwise be inert to the
compounds of formula I. The pH may be determined by taking a unit
dosage of the composition containing e.g. 20 mg of fluvastatin or
the equivalent amount of another compound falling under formula I
and dispersing or dissolving the composition in 10 to 100 ml of
water.
The pharmaceutically acceptable alkaline substance(s) which
comprise the alkaline medium may range from water-soluble to
sparingly soluble to essentially water-insoluble.
Examples of water-soluble alkaline substances capable of imparting
the requisite basicity include certain pharmaceutically acceptable
inorganic carbonate salts such as sodium or potassium carbonate,
sodium bicarbonate, or potassium hydrogen carbonate; phosphate
salts selected from, e.g., anhydrous sodium, potassium or calcium
dibasic phosphate, or trisodium phosphate; as well as alkali metal
hydroxides such as sodium, potassium, or lithium hydroxide; and
mixtures of the foregoing.
An example of a stabilized composition according to the invention
may comprise: 0.5 to 60 wt. % (weight %), typically 0.5 to 40 wt.
%, drug substance (e.g., fluvastatin); and 0.1 to 35 wt. %,
preferably 1-15 wt. %, of soluble carbonate compound, for example,
selected from sodium bicarbonate, sodium carbonate and mixtures
thereof.
Examples of water-insoluble or sparingly soluble alkaline
substances also potentially useful to comprise the stabilizing
alkaline medium in the compositions comprise compounds commonly
employed in antacid formulations (e.g., magnesium oxide, hydroxide
or carbonate; magnesium hydrogen carbonate; aluminum or calcium
hydroxide or carbonate; composite aluminum-magnesium compounds,
such as magnesium aluminum hydroxide): as well as pharmaceutically
acceptable salts of phosphoric acid such as tribasic calcium
phosphate; and mixtures thereof.
Of the above-mentioned alkaline substances, the "pharmaceutically
acceptable carbonate salts," by which is meant pharmaceutically
acceptable inorganic carbonate and bicarbonate salts, e.g., sodium
carbonate, sodium bicarbonate, calcium carbonate, and mixtures
thereof, have been found particularly effective to comprise the
alkaline medium.
Compositions also having particularly attractive storage stability
comprise, as an alkaline medium, both a water-soluble alkaline
excipient and a water-insoluble or sparingly soluble alkaline
excipient.
For example, substantial improvements in stability and other
advantages have been achieved by employing an alkaline medium
comprising a water-soluble carbonate salt and a water-insoluble
carbonate salt, especially, the combination of sodium bicarbonate
(or carbonate) with calcium carbonate.
Sodium bicarbonate advantageously serves to neutralize acidic
groups in the composition in the presence of moisture which may
adsorb onto particles of the composition during storage. The
calcium carbonate exerts a buffering action in the stored
composition, without apparent effect on drug release upon
ingestion. It has further been found that the carbonate salts
sufficiently stabilize the drug substance such that conventional
water-based preparative techniques, e.g. trituration with water or
wet granulation, can be utilized to prepare stabilized compositions
of the invention.
The calcium carbonate can be a precipitated or ground material, but
is preferably precipitated.
The alkaline medium will be present in the compositions in an
amount sufficient to impart a pH of e.g. at least 8, and preferably
at least 9, and as high as pH 10, to an aqueous solution or
dispersion of the composition. In general, the compositions of the
invention comprise from about 0.1 to 60 wt. % (typically, 0.5 to 40
wt. %) drug substance; and from about 0.1 to 60 wt. %, preferably
20 to 35 wt. %, alkaline medium.
The amount of a particular stabilizing excipient to be employed
will depend to some extent on the intended manufacturing process.
In compositions to be tableted, for example, calcium carbonate
should not exceed an amount which can be conveniently subjected to
compression, and will generally be used in combination with a more
readily compressible alkaline substance, e.g., sodium bicarbonate.
On the other hand, capsule dosage forms may comprise higher levels
of poorly compressible excipients, provided that the overall
composition remains sufficiently free-flowing and processible.
A solid unit dosage composition may have the ratio of water soluble
carbonate to insoluble carbonate from e.g. 1:40 to 2:1.
An exemplary tablet of the invention may comprise about 2:1 to 1:2
by weight calcium carbonate to sodium bicarbonate. A capsule
composition may comprise these excipients in a ratio of, for
example, 25:1 to 35:1 by weight.
In addition to the drug substance and alkaline medium, a filler is
also generally employed in the compositions to impart
processability. Potentially suitable filler materials are
well-known to the art (see, e.g., Remington's Pharmaceutical
Sciences, 18th Ed. (1990), Mack Publishing Co., Easton, Pa., pp.
1635-1636), and include lactose and other carbohydrates,
pregelatinized starch, e.g., starch 1500.RTM. (Colorcon Corp.),
corn starch, dicalcium phosphate, cellulose, microcrystalline
cellulose, sugars, sodium chloride, and mixtures thereof, of which
lactose, microcrystalline cellulose, pregelatinized starch, and
mixtures thereof, are preferred.
Owing to its superior disintegration and compression properties,
microcrystalline cellulose (Avicel.RTM., FMC Corp.), and mixtures
comprising microcrystalline cellulose and one or more additional
fillers, e.g., pregelatinized starch, are particularly useful.
The total filler is present in the compositions in an amount of
about 1 to 65 wt. %, based on the total composition.
Other ingredients which may be incorporated into the compositions
to facilitate processing and/or provide enhanced properties of the
product dosage form, include well-known tableting binders (e.g.,
gelatin, sugars, natural and synthetic gums, such as
carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone,
hydroxypropylmethylcellulose), microcrystalline cellulose, and
mixtures of the foregoing; disintegrants (e.g., cross-linked
carboxymethylcellulose, croscarmelose, crospovidone, sodium starch
glycolate), lubricants (e.g., magnesium stearate, hydrogenated
vegetable oil, carnauba wax and the like); flow agents (e.g.,
silicon dioxide), anti-adherents or glidants (e.g., talc) as well
as sweeteners, coloring mediums (e.g., iron oxide, aluminum lakes),
flavoring mediums, antioxidants, etc. Selection of a particular
ingredient or ingredients and the amounts used will be readily
determinable by one skilled in the art by reference to standard
procedures and practices for preparing tableted or encapsulated or
other dosage forms. In general, an effective amount of a tableting
binder will comprise about 1 to 10 wt. %, and preferably 1 to 5 wt.
%; anti-adherents or gildants, about 1 to 10 wt. %; disintegrants,
about 1 to 5 wt. %, and lubricants, about 0.1 to 2 wt. %, based on
the total composition.
Such compositions may be formulated by known means to provide
standard unitary oral dosages of compound, e.g., 5 mg, 10 mg, 20
mg, 40 mg, etc., in the form of capsules, tablets, pellets,
etc.
Enteric film coating materials may optionally be applied to oral
tablets, pellets or capsules to protect against premature
degradation of the drug substance by gastric acid prior to reaching
the intestinal absorption site. Examples of such materials are
well-known and include hydroxypropylmethylcellulose phthalate,
cellulose acetate phthalate, polyvinyl acetate phthalate,
methylcellulose phthalate, copolymerized methacrylic
acid/methacrylic acid methyl esters (e.g., Eudragit.RTM., Rohm
Pharma). The enteric coating is preferably applied to result in
about a 5 to 12, preferably 8 to 10, weight percent increase of the
capsule, pellet or tablet core.
Tableted compositions of the invention are desirably coated to
protect against moisture and light discoloration, and to mask the
bitter taste of the drug. Either the enteric coating may contain
opacifiers and colorants, or a conventional opaque film coating may
be applied to the tablet core, optionally after it has been coated
with an enteric substance.
Examples of suitable film formers in film coating formulations to
be applied to compositions of the invention comprise, e.g.,
polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol,
hydrophilic polymers such as hydroxypropylcellulose,
hydroxymethylcellulose, and hydroxypropylmethylcellulose or the
like, of which hydroxypropylmethylcellulose (e.g., Opadry
Yellow.sup.T, Colorcon Corp.) is preferred. Hydrophobic
film-formers which may be applied using an organic solvent vehicle
comprise, for example, ethyl cellulose, cellulose acetate,
polyvinyl alcohol-maleic anhydride copolymers, etc.
The film coating may be generally applied to achieve a weight
increase of the pellet or core or tablet of about 1 to 10 wt. %,
and preferably about 2 to 6 wt. %.
Other conventional enteric or film coating formulation ingredients
include plasticizers, e.g., polyethylene glycol (e.g. polyethylene
glycol 6000), triethylcitrate, diethyl phthalate, propylene glycol,
glycerin, butyl phthalate, in conventional amounts, as well as the
above-mentioned opacifiers such as titanium dioxide, and colorants,
e.g. iron oxide, aluminum lakes, etc.
The enteric or film coatings can be applied by conventional
techniques in a suitable coating pan or fluidized bed apparatus
using water and/or conventional organic solvents (e.g., methyl
alcohol, ethyl alcohol, isopropyl alcohol), ketones (acetone,
ethylmethyl ketone), chlorinated hydrocarbons (methylene chloride,
dichloroethane), etc.
A composition according to the invention comprises the following
(in weight percent based on the total composition):
0.1 to 60 wt. % (typically 0.5 to 40 wt. %) compound (e.g.,
fluvastatin), 0.1 to 60 wt. % alkaline stabilizing medium (e.g.,
carbonate salts), and 1 to 65 wt. % filler (e.g., microcrystalline
cellulose).
An example of such a composition comprises (in weight percent based
on the total composition): 0.5 to 60 wt. % HMG-CoA reductase
compound (e.g., fluvastatin), 10 to 55 wt. % (e.g., 10 to 35 wt. %)
alkaline medium (e.g., carbonate salts), and 10 to 65 wt. % (e.g.,
20 to 65 wt. %) filler (e.g., microcrystalline cellulose).
Another example of a composition according to the invention
comprises (in weight percent based on the total composition):
0.5 to 60 wt. %, drug compound (e.g., fluvastatin), 5 to 40 wt. %
(e.g., 10 to 40 wt. %) calcium carbonate, 0.5 to 20 wt. % (e.g.,
0.5 to 15 wt. %) sodium bicarbonate, and 10 to 65 wt. % filler
(e.g., microcrystalline cellulose).
An example of a capsule composition according to the invention
comprises (in weight percent based on the total composition):
0.5 to 60 wt. % (typically 0.5 to 40 wt. %) drug compound (e.g.,
fluvastatin), 25 to 40 wt. % calcium carbonate, 0.5 to 10 wt. %
sodium bicarbonate, and 20 to 35 wt. % microcrystalline cellulose,
and optional additional filler (e.g., pregelatinized starch) in an
amount of 15 to 30 wt. %.
An example of an tableted composition according to the invention
comprises (in weight percent based on the total composition):
0.5 to 60 wt. % drug compound (e.g., fluvastatin), 5 to 20 wt. %
calcium carbonate, 5 to 20 wt. % sodium bicarbonate, and 50 to 65
wt. % microcrystalline cellulose.
The stabilized compositions of the invention may be prepared by
various techniques and manufacturing processes generally known to
the art.
In preparing the compositions it is important that the drug
substance and the alkaline medium be brought into intimate
contacting association. Dry blending these components to achieve a
substantially homogeneous mixture (preferably prior to addition of
filler and remaining excipients), followed by a compression step,
can achieve the desired intimate contacting.
However, to obtain very stable formulations, an aqueous or other
solvent-based preparative process is preferably utilized, whereby
the drug substance and alkaline medium are blended together in the
presence of minor amounts of, e.g., water, to provide particles
containing the drug and alkaline substance in intimate admixture.
Given the hygroscopicity and moisture sensitivity of HMG-CoA
reductase inhibitor compounds such as fluvastatin, it is unexpected
that the drug substance is sufficiently stabilized by the alkaline
medium to resist degradation by such techniques.
In one embodiment of such a process, the drug and alkaline medium
are triturated with water, and the resulting particles are dried.
Filler and remaining excipients, which have been set aside to
comprise an "external phase" of said particles, are then blended
with the dried particles to result in a composition suitable for
encapsulation, tableting or the like.
In another embodiment of a solvent-based process which can assist
subsequent drying in a fluidized bed, the drug substance and
alkaline medium are wet granulated by known techniques, i.e.
blended in the moistened state, together with an amount of the
filler material. The thus-formed granules, after drying, are then
combined with any remaining filler and other set-asides, e.g.,
binder, lubricant, and can therefore be tableted, encapsulated, or
otherwise shaped into a dosage form.
It is important in order to achieve extended shelf life of the
compositions that the particles prepared by trituration or wet
granulation or other aqueous-based process be substantially
completely dried, i.e. to a weight loss on drying (L.O.D.) of not
greater than 3%, and preferably not greater than 2%.
Drying is conventionally performed by tray drying or in a fluidized
bed, preferably the latter. Drying is typically performed at about
50.degree. C. inlet temperature, and below 50% RH.
In preparing the compositions, the drug substance and the remaining
ingredients of the dosage form (except lubricant) are preferably
passed through 30 to 40 mesh screen prior to being triturated or
wet granulated, the drug substance generally being screened first
and then blended with the screened excipients. Additionally, the
dried particles or granules are passed through 18 to 20 mesh screen
for proper blending with the set asides.
Compositions to be tableted are typically passed through a smaller
screen, e.g., 24 mesh, before being combined with a lubricant and
subjected to compression; and this screening step generally
requires an additional drying step, whereby the wet particles or
granules obtained by trituration or granulation are dried to an
L.O.D. of 6-8%, then passed through 12 to 14 mesh screen, and then
redryed to an L.O.D. of 2-3%.
In an alternative preparative procedure to the above-described
trituration or wet granulation techniques, the drug substance and
the alkaline stabilizing medium can be co-lyophilized, i.e.
freeze-dried, from aqueous solution, advantageously as a step in
situ of the drug manufacturing process.
As exemplified in U.S. Pat. No. 4,739,073, which is incorporated by
reference herein, fluvastatin sodium, as well as the sodium salts
or other pharmaceutically acceptable salts of other HMG-CoA
reductase inhibitor compounds of the invention, is typically
prepared by hydrolyzing the corresponding ester compound with,
e.g., sodium hydroxide in ethanol solution. The ethanol or other
organic phase is then evaporated and water is added to the
remaining drug-containing phase to form an aqueous solution from
which (generally after extraction with an organic solvent), the
HMG-CoA reductase inhibitor compound is recovered by
lyophilization.
It has been found that a water-soluble stabilizing alkaline
substance such as sodium carbonate or bicarbonate or other alkaline
medium, can be added in situ to the above-described aqueous phase
comprising the fluvastatin or other HMG-CoA reductase inhibitor
compound, and upon subjecting this aqueous phase to a freeze-drying
procedure, there can be obtained particles comprising the drug
compound co-lyophilized with the added alkaline substance.
Very good contacting of the drug and stabilizer can thereby be
achieved, to the extent that stable compositions of the invention
may be prepared, for example, from the drug and sodium carbonate in
a weight ratio of about 10:1 to 100:1. For example, a
co-lyophilized composition of the invention comprising as low as
0.1% by weight sodium carbonate has been found effective to provide
a highly stabilized drug composition.
Lyophilization is carried out by conventional procedures and
equipment, by first reducing the temperature of the solution from
room temperature to below freezing, typically down to in the range
of about -45.degree. C., and applying a high vacuum, e.g., in the
range of about 3 mm Hg or less, and thereafter raising the
temperature to at or above room temperature, to result in
vaporization of the aqueous solvent. The recovered particles are
essentially free of solvent, and optimally comprise a substantially
homogeneous mixture of the drug and stabilizer.
The obtained particles can then be combined with other excipients,
e.g., filler, binder, lubricant, etc.
The compositions of the invention, obtained by any of the above
techniques, can be formed into a dosage form by techniques and
procedures well-known to the art, e.g., tableting, encapsulation,
pelleting, molding, etc.
As previously indicated, an enteric and/or film coating composition
can be applied to the dosage form for its particular benefits.
Enteric or film coating of a microcrystalline cellulose-based
tablet with a water-based film coating formulation is desirably
carried out at a bed temperature of 30.degree.-50.degree. C., an
inlet temperature of 50.degree.-80.degree. C. and a relative
humidity (RH) of less than 50%.
It is important for achieving optimal stability of the formulation
that the enteric and/or film coated dosage form be dried to a
moisture content which is not greater than 4% and preferably not
greater than 3%.
The resulting tableted or capsule dosage forms should be protected
during storage against thermal or light induced oxidation as well
as moisture contamination.
Capsules and tablets prepared from the compositions of the
invention have been found to have an attractive storage
stability.
The dosage forms are suitable for the intended use. Film-coated
tablets or capsules of the invention have a disintegration time of
about 10 to 30 minutes. Enteric coated tablets or capsules have a
disintegration time in general of about 30 minutes to about 6
hours.
Dosage regimens for treating hyperlipoproteinemia or
atherosclerosis by administering to a patient a compound of formula
Ia are set forth in U.S. Pat. No. 4,739,073 at col. 34, 11.20-54,
which is incorporated by reference. For example, the oral daily
dosage is indicated to be 0.1 to 10 mg./kg. body weight or, for
larger primates, 0.1 to 140 mg.
In addition to compositions comprising fluvastatin sodium, the
present invention is intended to cover compositions comprising
other HMG-CoA reductase inhibitor compounds of formula I herein,
including both the erythro racemate and its constituent isomers
(i.e. the 3R,5S and 3S,5R isomers, preferably the 3R,5S isomer).
Said compounds are disclosed, e.g., in the following commonly
assigned patents, published patent applications and publications
which are all hereby incorporated herein by reference:
U.S. Pat. No. 4,739,073, and EP-A-114,027 (R=indolyl and
derivatives thereof); EP-A-367,895 (R=pyrimidinyl and derivatives
thereof); U.S. Pat. No. 5,001,255 (R=indenyl and derivatives
thereof); U.S. Pat. No. 4,613,610 (R=pyrazolyl and derivatives
thereof); U.S. Pat. No. 4,851,427 (R=pyrrolyl and derivatives
thereof); U.S. Pat. Nos. 4,755,606 and 4,808,607 (R=imidazolyl and
derivatives thereof); U.S. Pat. No. 4,751,235 (R=indolizinyl and
derivatives thereof); U.S. Pat. No. 4,939,159 (R=azaindolyl and
derivatives thereof); U.S. Pat. No. 4,822,799 (R=pyrazolopyridinyl
and derivatives thereof); U.S. Pat. No. 4,804,679 (R=naphthyl and
derivatives thereof); U.S. Pat. No. 4,876,280 (R=cyclohexyl and
derivatives thereof); U.S. Pat. No. 4,829,081 (R=thienyl and
derivatives thereof); U.S. Pat. No. 4,927,851 (R=furyl and
derivatives thereof); U.S. Pat. No. 4,588,715 (R=phenylsilyl and
derivatives thereof); and F. G. Kathawala, Medicinal Research
Reviews, Vol. 11 (2), p.121-146 (1991), and F. G. Kathawala,
Atherosclerosis Research - Review, June 1992, p. B73-B85.
Further compounds of formula I are disclosed e.g. in EP-A-304,063
(R=quinolinyl and derivatives thereof); EP-A-330,057 and U.S. Pat.
Nos. 5,026,708 and 4,868,185 (R=pyrimidinyl and derivatives
thereof); EP-A-324,347 (R=pyridazinyl and derivatives thereof);
EP-A-300,278 (R=pyrrolyl or derivatives thereof); and U.S. Pat. No.
5,013,749 (R=imidazolyl and derivatives thereof).
Compounds suitable as active ingredients in the compositions are
those, wherein R is selected from indolyl, pyrimidinyl, indenyl,
pyrazolyl, pyrrolyl, imidazolyl, indolizinyl, pyrrolopyridine,
pyrazolopyridine, quinolinyl, phenylsilylphenyl, naphthyl,
cyclohexyl, phenylthienyl, phenylfuryl and pyridazinyl radical and
derivatives thereof. Preferred are those compounds of formula I
wherein R is selected from indolyl, pyrimidinyl, indenyl,
quinolinyl and pyridinyl radicals and derivatives thereof and X is
(E)--CH.dbd.CH--.
Specific examples of compounds disclosed in the above or other
publications, which are HMG-CoA reductase compounds suitable to be
employed as the drug active agent in the compositions of the
invention, comprise the following sodium salts, or other
pharmaceutically acceptable salts:
erythro-3R,5S-(E)-7-[4-(4-fluorophenyl)-6-(1-methylethyl)-2-dimethylamino-p
yrimidin-5-yl]-3,5-dihydroxy-6-heptenoic acid, sodium salt;
erythro-(.+-.)-(E)-7-[3-(4-fluorophenyl)-spiro[cyclopentane-1,1'-1H-inden]-
2'-yl]-3,5-dihydroxy-6-heptenoic acid, sodium salt;
erythro-3R,5S-(E)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-indolizin-2-yl]-3
,5-dihydroxy-6-heptenoic acid, sodium salt;
erythro-3R,5S-(E)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-pyrrolo[2,3-b]
pyridin-2-yl]-3,5-dihydroxy-6-heptenoic acid, sodium salt;
erythro-3R,5S-(E)-7-[4-(4-fluorophenyl)-2-(1-methylethyl)-quinolin-3-yl]-3,
5-dihydroxy-6-heptenoic acid, sodium salt;
erythro-3R,5S-(E)-7-[1-(4-fluorophenyl)-3-(1-methylethyl)-4-oxo-1,4-dihydro
-quinolin-2-yl]-3,5-dihydroxy-6-heptenoic acid, sodium salt;
erythro-3R,5S-(E)-7-[4-(4-fluorophenyl)-6-(1-methylethyl)-3-methyl-1H-pyraz
olo[3,4-b]pyridin-5-yl]-3,5-dihydroxy-6-heptenoic acid, sodium
salt;
erythro-3R,5S-(E)-7-[3-(1-methylethyl)-5,6-diphenyl-pyridazin-4-yl]-3,5-dih
ydroxy-6-heptenoic acid, sodium salt;
erythro-3R,5S-(E)-7-[4-(4-fluorophenyl)-6-(1-methylethyl)-2-phenylpyrimidin
-5-yl]-3,5-dihydroxy-6-heptenoic acid, sodium salt;
erythro-3R,5S-(E)-7-[4-(4-fluorophenyl)-1-(1-methylethyl)-3-phenyl-2-oxo-2,
3-dihydroimidazol-5-yl]-3,5-dihydroxy-6-heptenoic acid, sodium
salt;
erythro-3R,5S-(E)-7-[4-(4-fluorophenyl)-2-(1-methylethyl)-1-oxo-1,2-dihydro
-quinolin-3-yl]-3,5-dihydroxy-6-heptenoic acid, sodium salt;
erythro-(.+-.)-(E)-7-[4-(4-fluorophenyl)-2-(1-methylethyl)-quinolin-3-yl]-3
,5-dihydroxy-6-heptenoic acid, sodium salt;
erythro-(.+-.)-(E)-7-[1-(4-fluorophenyl)-3-(1-methylethyl)-pyrrolo
[2,1-a]isoquinolin-2-yl]-3,5-dihydroxy-6-heptenoic acid sodium
salt;
erythro-(.+-.)-(E)-7-[4-cyclopropyl-6-(4-fluorophenyl)-2-(4-methoxyphenyl)-
pyrimidin-5-yl]-3,5-dihydroxy-6-heptenoic acid, sodium salt;
erythro-3R,5S-(E)-7-[4-(4-fluorophenyl)-2,6-dimethylpyrimidin-5-yl]-3,5-dih
ydroxy-6-heptenoic acid, sodium salt;
erythro-3R,5S-(E)-7-[4-(4-fluorophenyl)-6-methyl-2-phenyl-pyrimidin-5-yl]-3
,5-dihydroxy-6-heptenoic acid, sodium salt;
erythro-3R,5S-(E)-7-[4-(3,5-dimethylphenyl)-6-methyl-2-phenyl-pyrimidin-5-y
l]-3,5-dihydroxy-6-heptenoic acid, sodium salt;
erythro-(.+-.)-(E)-7-[3,4-bis(4-fluorophenyl)-6-(1-methylethyl)-pyridazin-5
-yl]-3,5-dihydroxy-6-heptenoic acid, sodium salt;
erythro-(.+-.)-(E)-7-[1-(4-fluorophenyl)-3-(1-methylethyl)-5-phenyl-1H-pyrr
ol-2-yl]-3,5-dihydroxy-6-heptenoic acid, sodium salt;
erythro-(.+-.)-(E)-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyl-1H-tet
razol-5-yl)-6,8-nonadienoic acid, sodium salt;
erythro-(.+-.)-(E)-3,5-dihydroxy-9,9-diphenyl-6,8-nonadienoic acid,
sodium salt;
erythro-(.+-.)-(E)-7-[4-(4-fluorophenyl)-1,2-bis(1-methylethyl)-3-phenyl-py
rrol-2-yl]-3,5-dihydroxy-6-heptenoic acid, sodium salt;
erythro-3R,5S-(E)-7-[4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazol-
1-yl]-3,5-dihydroxy-6-heptenoic acid, sodium salt;
erythro-3R,5S-(E)-7-[4-(4-fluorophenyl)-2,6-bis(1-methylethyl)-5-methoxymet
hyl-pyridin-3-yl]-3,5-dihydroxy-6-heptenoic acid, sodium salt;
erythro-(.+-.)-(E)-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-pyridin-3
-yl]-3,5-dihydroxy-6-heptenoic acid, sodium salt;
erythro-(.+-.)-(E)-[2-(4-fluorophenyl)-4,4,6,6-tetramethyl-cyclohexen-1-yl]
-3,5-dihydroxy-6-heptenoic acid, sodium salt;
erythro-(.+-.)-(E)-7-[4-(4-fluorophenyl)-2-(1-methylethyl)-quinolin-3-yl]-3
,5-dihydroxy-6-heptenoic acid, sodium salt;
erythro-(.+-.)-(E)-7-[4-(4-fluorophenyl)-2-cyclopropyl-quinolin-3-yl]-3,5-d
ihydroxy-6-heptenoic acid, sodium salt;
The compounds of formula I are HMG-CoA reductase inhibitors, i.e.,
cholesterol biosynthesis inhibitors, and, therefore, they are
useful for the treatment of hyperlipoproteinemia and
atherosclerosis as disclosed in the aforementioned patents,
published applications and publications which have been
incorporated by reference.
The following Examples are intended to illustrate the invention in
various of its embodiments without being limitative in any way
thereof.
EXAMPLE 1
A 20 mg No. 3 size oral fluvastatin capsule is prepared comprising
the following formulation:
TABLE 1 ______________________________________ Ingredient Amount
(mg) ______________________________________ fluvastatin 21.06
calcium carbonate, USP.sup.a 62.84 sodium bicarbonate, USP 2.00
microcrystalline cellulose, NF.sup.b 23.35 pregelatinized starch,
NF.sup.c 20.95 purified water, USP q.s.* set-asides:
microcrystalline cellulose 33.88 pregelatinized starch 20.95 talc,
USP 9.43 magnesium stearate, NF 1.05
______________________________________ .sup.a heavy, precipitated
.sup.b Avicel, PH 102, FMC Corp. .sup.c Starch 1500, Colorcon Corp.
*removed during processing
(a) The fluvastatin, 2 mg sodium bicarbonate, 62.84 mg calcium
carbonate, 23.35 mg microcrystalline cellulose, and 20.95 mg
pregelatinized starch, are mixed for five minutes and the mixture
is passed through a 40 mesh screen and blended for another three
minutes.
(b) Water is added to the mixture, while blending for about four
minutes, to form a wet granulation.
(c) The wet granulation is dried in a fluid bed dryer at 50.degree.
C. inlet temperature to an L.O.D. of 1.59%.
(d) The dried granules are passed through a 20 mesh screen and
blended with the microcrystalline cellulose and pregelatinized
starch set-asides for about ten minutes. Talc and magnesium
stearate (each pre-screened on 60 mesh bolting cloth) are added to
the mixture while blending for about 5 minutes.
The resulting composition has an L.O.D. of 2.65%.
A dispersion of the composition in 10-100 ml. of water has a pH of
10.
(e) A blue opaque capsule is filled with the composition and
polished manually with salt.
The capsule meets a dissolution specification of 75% in 30 minutes
by the USP paddle method.
The drug is found to be 99% intact after 18 months at 30.degree. C.
in a light protected, moisture-resistant environment.
EXAMPLE 2
In the same manner as described in Example 1, 40 mg double-sized
No. 3 capsules are prepared employing twice the amounts of
ingredients indicated in Table 1.
EXAMPLE 3
In the same manner as described in Example 1, 10 mg No. 3
fluvastatin capsules are prepared except that an additional 10 mg
of microcrystalline cellulose is utilized.
EXAMPLE 4
A 20 mg oral fluvastatin tablet is prepared comprising the
following formulation:
TABLE 2 ______________________________________ Ingredient Amount
(mg) ______________________________________ fluvastatin 21.06
calcium carbonate, USP 25.00 sodium bicarbonate, USP 25.00
microcrystalline cellulose, NF.sup.d 118.94 croscarmellose sodium,
NF.sup.e 3.00 polyvinylpyrrolidone, USP.sup.f 6.00 magnesium
stearate, NF 1.00 purified water, USP q.s.*
______________________________________ .sup.d Avicel PH 101 (FMC
Corp.) .sup.e AcDi-Sol (FMC Corp.) .sup.f Kollidon 30 (BASF Corp.)
*removed during processing
(a) The fluvastatin, calcium carbonate, sodium bicarbonate,
microcrystalline cellulose, polyvinyl pyrrolidone, and
croscarmellose sodium, are each passed through a 40 mesh screen,
and then combined and mixed for 3 minutes, and the resulting
mixture is passed through a 40 mesh screen, and mixing is continued
for 2 minutes.
(b) Water is added to the resulting mixture, while blending for
about 5 minutes to form a wet granulation.
(c) The granulation is dried in a fluid bed dryer with inlet
temperature of 50.degree. C. until L.O.D. of the granules is 6 to
8%. The granules are passed through a 14 mesh screen and redried
until L.O.D. is not greater than 2.5%. The dried granules are
passed through a 24 mesh screen, and blended for three minutes.
(d) Magnesium stearate, passed through a 60 mesh bolting cloth, is
blended into the mixture for five minutes.
The resulting composition has an L.O.D. of not greater than 2%.
A dispersion of the composition in 10-100 ml of water has a pH of
10.
(e) The resulting light yellow colored composition is tableted
using an 8 mm punch, to form a 200 mg tablet core.
(f) A hydroxypropylmethylcellulose film coating formulation, Opadry
Yellow.sup.T, YS-1-6347-G, Colorcon Corp. (10% aqueous suspension),
is applied to the tablet core in a fluidized bed with an inlet
temperature set at 70.degree.-75.degree. C., to result in a 5-6%
tablet weight gain.
The resulting tablet meets a dissolution specification of 75% in 30
minutes by the USP paddle method.
The drug is found to be 99% intact after 18 months at 30.degree. C.
in a light protected, moisture-resistant environment.
EXAMPLE 5
In the same manner as described in Example 4, 40 mg fluvastatin
tablets are prepared wherein the ingredients of the tablet core are
present in twice the amounts indicated in Example 4.
EXAMPLE 6
In the same manner as described in Example 4, 10 mg fluvastatin
tablets are prepared wherein the ingredients of the tablet core are
present in half the amounts indicated in Example 4.
EXAMPLE 7
A fluvastatin tablet core or capsule prepared as described in any
one of the above Examples is coated in a fluidized bed at a bed
temperature of 30.degree.-50.degree. C., inlet temperature of
50.degree.-80.degree. C., and a relative humidity of less than 50%
with an enteric coating formulation comprising Eudragit.RTM. (Rohm
Pharma) or, alternatively, hydroxypropylmethylcellulose phthalate,
to result in a weight percent increase of about 5-12%.
EXAMPLE 8
A composition according to the invention is prepared as described
in any one of the above Examples which comprises
erythro-3R,5S-(E)-7-[4-(4-fluorophenyl)-6-(1-methylethyl)-2-dimethylamino-
pyrimidin-5-yl]-3,5-dihydroxy-6-heptenoic acid, sodium salt, or its
3R,5S isomer, as the active agent.
EXAMPLE 9
A composition according to the invention is prepared as described
in any one of the above Examples which comprises
erythro-(.+-.)-(E)-7-[3-(4-fluorophenyl)-spiro[cyclopentane-1,1'-1H-inden]
-2'-yl]-3,5-dihydroxy-6-heptenoic acid, sodium salt, or its 3R,5s
isomer, as the active agent.
EXAMPLE 10
A composition according to the invention is prepared as described
in any one of the above Examples which comprises
erythro-3R,5S-(E)-7-[4-(4-fluorophenyl)-2,6-bis(1-methylethyl)-5-methoxyme
thyl-pyridin3-yl]-3,5-dihydroxy-6-heptenoic acid, sodium salt, or
its racemate, as the active agent.
EXAMPLE 11
A composition according to the invention is prepared as described
in any one of the above Examples which comprises
erythro-(.+-.)-(E)-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-pyridin-
3-yl]-3,5-dihydroxy-6-heptenoic acid, sodium salt, or its 3R,5S
isomer, as the active agent.
EXAMPLE 12
A composition according to the invention is prepared as described
in any one of the above Examples which comprises
erythro-(.+-.)-(E)-7-[4-(4-fluorophenyl)-2-(1-methylethyl)-quinolin-3-yl]-
3,5-dihydroxy-6-heptenoic acid, sodium salt, or its 3R,5S isomer,
as the active agent.
EXAMPLE 13
A composition according to the invention is prepared as described
in any one of the above Examples which comprises
erythro-(.+-.)-(E)-7-[4-(4-fluorophenyl)-2-cyclopropyl-quinolin-3-yl]-3,5-
dihydroxy-6-heptenoic acid, sodium salt, or its 3R,5S isomer, as
the active agent.
* * * * *